Cost-Effectiveness of a JAK1/JAK2 Inhibitor vs a Biologic Disease-Modifying Antirheumatic Drug (bDMARD) in a Treat-to-Target Strategy for Rheumatoid Arthritis.
Baricitinib is a janus kinase (JAK1/JAK2) inhibitor developed for the treatment of patients suffering from rheumatoid arthritis (RA). Treating RA to the target of remission is current common practice. Cost-effectiveness of different treat-to-target (T2T) strategies, especially ones including new treatments is important for development and preference policy for treatment centers. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines are currently unclear about preference between a JAK1/JAK2 versus a biological disease-modifying antirheumatic drug (bDMARD). The main goal of this paper was to evaluate the cost-effectiveness of baricitinib versus first biological for methotrexate inadequate responders in a T2T strategy using a Markov model that incorporates hospital costs as well as societal costs. Costs and utilities over five years were compared between the two strategies. A Monte Carlo simulation model was developed to conduct cost-utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-erythrocyte sedimentation rate (ESR) categories. Effectiveness of baricitinib was retrieved from randomized controlled trials. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from the Dutch RhEumatoid Arthritis Monitoring (DREAM) cohorts. Annual discount rates of 1.5% for utility and 4% for costs were used. Probabilistic sensitivity analysis was employed to incorporate uncertainty and assess robustness of the results. Probabilistic sensitivity analysis results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe RA populations. Results suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.


In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function.
Manganese (Mn) is an essential metal for development and metabolism. However, exposures to high Mn levels may be toxic, especially to the central nervous system (CNS). Neurotoxicity is commonly due to occupational or environmental exposures leading to Mn accumulation in the basal ganglia and a Parkinsonian-like disorder. Younger individuals are more susceptible to Mn toxicity. Moreover, early exposure may represent a risk factor for the development of neurodegenerative diseases later in life. The present study was undertaken to investigate the developmental neurotoxicity in an in vivo model of immature rats exposed to Mn (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN12. Neurochemical analysis was carried out on PN14. We focused on striatal alterations in intracellular signaling pathways, oxidative stress and cell death. Moreover, motor alterations as a result of early Mn exposure (PN8-12) were evaluated later in life at 3-, 4- and 5-weeks-of-age. Mn altered in a dose-dependent manner the activity of key cell signaling elements. Specifically, Mn increased the phosphorylation of DARPP-32-Thr-34, ERK1/2 and AKT. Additionally, Mn increased reactive oxygen species (ROS) production and caspase activity, and altered mitochondrial respiratory chain complexes I and II activities. Mn (10 and 20 mg/kg) also impaired motor coordination in the 3(rd), 4(th) and 5(th) week of life. Trolox™, an antioxidant, reversed several of the Mn altered parameters, including the increased ROS production and ERK1/2 phosphorylation. However, Trolox™ failed to reverse the Mn (20 mg/kg)-induced increase in AKT phosphorylation and motor deficits. Additionally, Mn (20 mg/kg) decreased the distance, speed and grooming frequency in an open field test; Trolox™ blocked only the decrease of grooming frequency. Taken together, these results establish that short-term exposure to Mn during a specific developmental window (PN8-12) induces metabolic and neurochemical alterations in the striatum that may modulate later-life behavioral changes. Furthermore, some of the molecular and behavioral events, which are perturbed by early Mn exposure are not directly related to the production of oxidative stress.


Prediction rules for the detection of coronary artery plaques: evidence from cardiac CT.
To evaluate spatial plaque distribution patterns in coronary arteries based on computed tomography coronary angiography data sets and to express the learned patterns in prediction rules. An application is proposed to use these prediction rules for the detection of initially missed plaques. Two hundred fifty two consecutive patients with chronic coronary artery disease underwent contrast-enhanced dual-source computed tomography coronary angiography for clinical indications. Coronary artery plaques were manually labeled on a 16-segment coronary model and their position (ie, segments and bifurcations) and composition (ie, calcified, mixed, or noncalcified) were noted. The frequent itemset mining algorithm was used to statistically search for plaque distribution patterns. The patterns were expressed as prediction rules: given plaques at certain locations as conditions, a prediction rule gave evidence--with a certain confidence value--for a plaque at another location within the coronary artery tree. Prediction rules with the highest confidence values were evaluated and described. Furthermore, to improve manual plaque detection, all prediction rules were applied on the patient data to search for segments with potentially missed plaques. These segments were then reviewed in a second, guided reading for the existence of plaques. The same number of segments was also determined by a weighted random approach to evaluate the quality of prediction resulting from frequent itemset mining. In 200 of 252 (79.4%) patients, at least one coronary plaque (range, 1-22 plaques) was found. In total 1229 plaques (990 calcified, 80.6%; 227 mixed, 18.5%; 12 noncalcified, 1%) distributed, over 916 coronary segments and 507 vessels were manually labeled. Four plaque distribution patterns were identified: 20.6% of the patients had no plaques at all; 31.7% had plaques in the left coronary artery tree; 46.4% had plaques both in left and right coronary arteries, whereas 1.2% of the patients had plaques solely in the right coronary artery (RCA). General rules were found predicting plaques in the left anterior descending artery (LAD), given plaques in segments of the RCA or in the left main artery. Further general rules predicted plaques in the LAD, given plaques in the circumflex artery. In the guided review, the segment selection based on the prediction rules from frequent itemset mining performed significantly better (P < 0.001) than the weighted random approach by revealing 48 initially missed plaques. This study demonstrates spatial plaque distribution patterns in coronary arteries as determined with cardiac CT. Use of the frequent itemset mining algorithm yielded rules that predicted plaques at certain sites given plaques at other sites of the coronary artery tree. Use of these prediction rules improved the manual labeling of coronary plaques as initially missed plaques could be predicted with the guided review.


Online Self-Management Support for Family Caregivers Dealing With Behavior Changes in Relatives With Dementia (Part 2): Randomized Controlled Trial.
Online contacts with a health professional have the potential to support family caregivers of people with dementia. The goal of the research was to study the effects of an online self-management support intervention in helping family caregivers deal with behavior changes of a relative with dementia. The intervention-involving among others personal email contacts with a dementia nurse-was compared with online interventions without these email contacts. A randomized controlled trial was conducted with 81 family caregivers of people with dementia who live at home. Participants were randomly assigned to a (1) major self-management support intervention consisting of personal email contacts with a specialist dementia nurse, online videos, and e-bulletins; (2) medium intervention consisting only of online videos and e-bulletins; or (3) minor intervention consisting of only the e-bulletins. The primary outcome was family caregivers' self-efficacy in dealing with behavior changes of the relative with dementia. Secondary outcomes were family caregivers' reports of behavior problems in the people with dementia and the quality of the relationship between the family caregiver and the person with dementia. Measurements were performed at the baseline and at 6 (T1) and 12 weeks (T2) after the baseline. A mixed-model analysis was conducted to compare the outcomes of the 3 intervention arms. Family caregivers participating in the major intervention involving email contacts showed no statistically significant differences in self-efficacy after the intervention compared with the minor intervention involving only e-bulletins (difference -0.02, P=.99). In the adjusted analysis, the medium intervention (involving videos and e-bulletins) showed a negative trend over time (difference -4.21, P=.09) and at T1 (difference -4.71, P=.07) compared with the minor intervention involving only e-bulletins. No statistical differences were found between the intervention arms in terms of the reported behavior problems and the quality of the relationship between the family caregiver and the person with dementia. The expectation that an online self-management support intervention involving email contacts would lead to positive effects and be more effective than online interventions without personal email contacts was not borne out. One explanation might be related to the fact that not all family caregivers who were assigned to that intervention actually made use of the opportunity for personal email contact. The online videos were also not always viewed. To obtain more definite conclusions, future research involving extra efforts to reach higher use rates is required. Netherlands Trial Registry NTR6237; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6237 (Archived by WebCite at http://www.webcitation.org/6v0S4fxTC). RR2-10.2196/resprot.8365.


Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing.
The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus, replacing laboratory animal models used currently. Thirty-six experts from academia, industry and regulatory bodies present here the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies, as well as various national and international programs are highlighted. Finally, a roadmap into the future is outlined, to allow for more predictive and regulatory-accepted substance testing on a global scale.


Thymus involution and cerebral white matter damage in extremely low gestational age neonates.
Among newborns who die, those who have cerebral white matter damage are more likely than others to have thymus involution and low thymus weights. We sought to evaluate in a population of preterm newborns who did not die if those who developed a cerebral white matter damage (as defined by an echolucency) are more likely than others to have thymus involution as assessed on chest radiographs. The 89 infants whose data were evaluated were born before the 28th week of gestation, had at least one chest radiograph within the first 2 days of life (to determine thymus size), and at least one cranial ultrasonogram to assess for white matter echolucency. Eighty-five percent of these infants had a small thymus within the first 2 weeks of life. Median time to thymus involution in those born before the 26th week of gestation was 36 h, and in those born during or after the 26th week of gestation was 140 h. Infants who developed involution before the median time in their respective gestational age groups were classified as early involuters (group 1) and were compared to their peers with late/no involution (group 2). Infants with an echolucency were more likely to have had early involution than infants without an echolucency (89% vs. 44%) (p = 0.01). This relationship was not distorted by potential confounders. The echolucency odds ratio associated with early thymus involution was consistently above 8 in all strata of the sample. These results are consistent with the possibility that early thymus involution and neonatal white matter damage are not independent phenomena and may have common antecedents.


Synthesis of copper ion incorporated horseradish peroxidase-based hybrid nanoflowers for enhanced catalytic activity and stability.
In this study, we report the preparation, catalytic activity and stability of a hybrid nanoflower (hNF) formed from horseradish peroxidase (HRP) enzyme and copper ions (Cu(2+)). We studied the morphology of hNFs as a function of the concentrations of copper (Cu(2+)) ions, chloride ions (Cl(-)) and HRP enzyme, the pH of the buffer solution (phosphate buffered saline), and the temperature of the reaction. The effects of morphology on the catalytic activity and stability of hNFs were evaluated by oxidation of guaiacol (2-methoxyphenol) to colored 3,3-dimethoxy-4,4-diphenoquinone in the presence of hydrogen peroxide (H2O2). The enhanced activity of hNFs synthesized (from 0.02 mg mL(-1) HRP in 10 mM PBS (pH 7.4) at +4 °C) was 17 595 U mg(-1), which was ∼300% higher than free HRP in PBS, where it achieved an activity of 5952 U mg(-1). In terms of stability, these hNFs stored in PBS buffer at +4 °C and room temperature (RT = 20 °C) lost 4% and 20%, respectively, of their initial catalytic activities within 30 days. Finally, we demonstrated that these hNFs can be utilized as sensors for the detection of dopamine.


Accommodation needs for carers of and adults with intellectual disability in regional Australia: their hopes for and perceptions of the future.
This article provides an in-depth investigation of the accommodation circumstances of a population of aging adults with intellectual disability living at home with parents or in supported accommodation in an Australian regional centre. Given the ageing of both the carer and adult population with intellectual disability our research explored the accommodation needs and perceptions of future lifestyle issues from the perspective of both the carers and the adults with intellectual disability. This study aimed to describe these accommodation circumstances related to a regional/rural location and did not make direct comparisons with urban/metropolitan situations. A mixed methods approach, specifically an explanatory design, participant selection model was utilised for the overall study. This article reports on the qualitative study consisting of data from both free response open-ended survey questions and semi-structured interviews with selected adults with intellectual disability and their carers. This study explored and described participants' experiences and perceptions regarding their accommodation needs and future lifestyle issues. A purposive sampling technique was used to identify a representative sample of participants for interviews. The interview questions were guided by the results of the quantitative first study phase. Data were analysed by content analysis for major themes emerging from the interview and free response survey data. A total of 146 carers (mean age 61.5 years; range 40-91 years) and 156 adults with intellectual disability (mean age 37.2 years; range 18-79 years) participated in the study. Data saturation was reached after 10 interviews were undertaken with carers (mean age 60 years) and 10 with adults with intellectual disability (no age criteria applied). Six major themes were identified: ageing, family issues, living at home, living away from home, government support and funding, and future needs. The perceptions and views of both adults with intellectual disability and their carers around these major themes are reported and discussed. This study indicates that there is a lack of suitable, available, supported accommodation for people aged 18 years and older with intellectual disability in this Australian regional centre. Consequently, aging parents caring at home have little choice but to continue in their caring role. For those caring away from home, existing services are decreasingly seen as fitting the ideal life they want for the person with intellectual disability for whom they care. The told experiences, perceptions and views of older carers of and adults with intellectual disability have highlighted their increasing vulnerability to the 'disability system'. The findings suggest that government and disability services must acknowledge the changing needs of people with intellectual disability in connection with their advancing age and the urgency of increasing care needs due to the advancing age of their carer's. The overwhelming feeling is that the carer's voice will only be heard when the situation reaches crisis point. For many carers and their families this has already occurred.


Observational study of regional aortic size referenced to body size: production of a cardiovascular magnetic resonance nomogram.
Cardiovascular magnetic resonance (CMR) is regarded as the gold standard for clinical assessment of the aorta, but normal dimensions are usually referenced to echocardiographic and computed tomography data and no large CMR normal reference range exists. As a result we aimed to 1) produce a normal CMR reference range of aortic diameters and 2) investigate the relationship between regional aortic size and body surface area (BSA) in a large group of healthy subjects with no vascular risk factors. 447 subjects (208 male, aged 19-70 years) without identifiable cardiac risk factors (BMI range 15.7-52.6 kg/m2) underwent CMR at 1.5 T to determine aortic diameter at three levels: the ascending aorta (Ao) and proximal descending aorta (PDA) at the level of the pulmonary artery, and the abdominal aorta (DDA), at a level 12 cm distal to the PDA. In addition, 201 of these subjects had aortic root imaging, allowing for measurements at the level of the aortic valve annulus (AV), aortic sinuses and sinotubular junction (STJ). Normal diameters (mean ±2 SD) were; AV annulus male(♂) 24.4 ± 5.4, female (♀) 21.0 ± 3.6 mm, aortic sinus♂ 32.4 ± 7.7, ♀27.6 ± 5.8 mm, ST-junction ♂25.0 ± 7.4, ♀21.8 ± 5.4 mm, Ao ♂26.7 ± 7.7, ♀25.5 ± 7.4 mm, PDA ♂20.6 ± 5.6, +18.9 ± 4.0 mm, DDA ♂17.6 ± 5.1, ♀16.4 ± 4.0 mm. Aortic root and thoracic aortic diameters increased at all levels measured with BSA. No gender difference was seen in the degree of dilatation with increasing BSA (p>0.5 for all analyses). Across both genders, increasing body size is characterized by a modest degree of aortic dilatation, even in the absence of traditional cardiovascular risk factors.


Optimisation of a system for the co-translational incorporation of a keto amino acid and its application to a tumour-specific Anticalin.
The bioorthogonal keto group has attracted interest for the site-specific chemical conjugation of recombinant proteins under mild conditions, e.g. with aminooxy-functionalised fluorescent probes, radiometal chelates, toxins or polymers. However, the cotranslational incorporation of the corresponding non-canonical amino acid p-acetyl-L-phenylalanine (Apa) into proteins expressed in Escherichia coli by means of amber suppression using a previously described system with a mutated tRNA and an engineered tyrosyl-tRNA synthetase from Methanococcus jannaschii shows limited efficiency and considerable promiscuity towards endogenous amino acids. Employing a one-plasmid system that encodes all three components required for selection, i.e. the modified aminoacyl-tRNA synthetase (aaRS), the cognate amber suppressor tRNA and the enhanced green fluorescent protein equipped with an amber stop codon and serving as reporter, we have generated an Apa-specific aaRS&tRNA pair with considerably improved efficiency (17-fold increased expression) and also fidelity (6-fold). To this end, both the aaRS and the tRNA were subjected to doped random mutagenesis and selection in altogether four evolutionary cycles using fluorescence-activated bacterial cell sorting as well as automated screening of microcultures. The resulting aaRS&tRNA pair was applied to the functionalisation of an Anticalin with specificity towards oncofetal fibronectin by introducing a keto group at a permissible site for subsequent conjugation with a fluorescent dye, thus allowing visualisation of this tumour target under the microscope.


Sexual torture of men in Croatia and other conflict situations: an open secret.
Sexual torture constitutes any act of sexual violence which qualifies as torture. Public awareness of the widespread use of sexual torture as a weapon of war greatly increased after the war in the former Yugoslavia in the early 1990s. Sexual torture has serious mental, physical and sexual health consequences. Attention to date has focused more on the sexual torture of women than of men, partly due to gender stereotypes. This paper describes the circumstances in which sexual torture occurs, its causes and consequences, and the development of international law addressing it. It presents data from a study in 2000 in Croatia, where the number of men who were sexually tortured appears to have been substantial. Based on in-depth interviews with 16 health professionals and data from the medical records of three centres providing care to refugees and victims of torture, the study found evidence of rape and other forced sexual acts, full or partial castration, genital beatings and electroshock. Few men admit being sexually tortured or seek help, and professionals may fail to recognise cases. Few perpetrators have been prosecuted, mainly due to lack of political will. The silence that envelopes sexual torture of men in the aftermath of the war in Croatia stands in strange contrast to the public nature of the crimes themselves.


Kaposi's sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression.
In vitro Kaposi's sarcoma-associated herpesvirus (KSHV) infection of primary human dermal microvascular endothelial (HMVEC-d) cells and human foreskin fibroblast (HFF) cells is characterized by the induction of preexisting host signal cascades, sustained expression of latency-associated genes, transient expression of a limited number of lytic genes, and induction of several cytokines, growth factors, and angiogenic factors. Since NF-kappaB is a key molecule involved in the regulation of several of these factors, here, we examined NF-kappaB induction during de novo infection of HMVEC-d and HFF cells. Activation of NF-kappaB was observed as early as 5 to 15 min postinfection by KSHV, and translocation of p65-NF-kappaB into nuclei was detected by immunofluorescence assay, electrophoretic mobility shift assay, and p65 enzyme-linked immunosorbent assay. IkappaB phosphorylation inhibitor (Bay11-7082) reduced this activation significantly. A sustained moderate level of NF-kappaB induction was seen during the observed 72 h of in vitro KSHV latency. In contrast, high levels of ERK1/2 activation at earlier time points and a moderate level of activation at later times were observed. p38 mitogen-activated protein kinase was activated only at later time points, and AKT was activated in a cyclic manner. Studies with UV-inactivated KSHV suggested a role for virus entry stages in NF-kappaB induction and a requirement for KSHV viral gene expression in sustained induction. Inhibition of NF-kappaB did not affect target cell entry by KSHV but significantly reduced the expression of viral latent open reading frame 73 and lytic genes. KSHV infection induced the activation of several host transcription factors, including AP-1 family members, as well as several cytokines, growth factors, and angiogenic factors, which were significantly affected by NF-kappaB inhibition. These results suggest that during de novo infection, KSHV induces sustained levels of NF-kappaB to regulate viral and host cell genes and thus possibly regulates the establishment of latent infection.


The effect of mesenchymal stromal cell-hyaluronic acid hydrogel constructs on immunophenotype of macrophages.
During the past several years, multipotent mesenchymal stromal cells (MSCs) have rapidly moved from in vitro and animal studies into clinical trials as a therapeutic modality potentially applicable to a wide range of disorders. It has been proposed that ex vivo culture-expanded MSCs exert their tissue regeneration potential through their immunomodulatory and anti-inflammatory properties, and paracrine effects more than their ability to differentiate into multiple tissue lineages. Since extracellular matrix (ECM) deposition and tissue support is also one of many physiological roles of MSCs, there is increasing interest in their potential use for tissue engineering, particularly in combination with ECM-based scaffolds such as hyaluronic acid (HA). We investigated the effect of MSCs on immunophenotype of macrophages in the presence of an HA-hydrogel scaffold using a unique 3D coculture system. MSCs were encapsulated in the hydrogel and peripheral blood CD14+ monocyte-derived macrophages plated in direct contact with the MSC-gel construct. To determine the immunophenotype of macrophages, we looked at the expression of cell surface markers CD14, CD16, CD206, and human leukocyte antigen (HLA)-DR by flow cytometry. MSCs and macrophages cultured on the HA-hydrogel remained viable and were able to be recovered from the construct. There was a significant difference in the immunophenotype observed between monocyte-derived macrophages cultured on the HA scaffold compared to tissue culture polystyrene. Macrophages cultured on gels with MSCs expressed lower CD16 and HLA-DR with higher expression of CD206, indicating the least inflammatory profile overall, compatible with the immunophenotype of alternatively activated macrophages. Development of macrophages, with this immunophenotype, upon interaction with the MSC-hydrogel constructs may play a potentially significant role in tissue repair when using a cellular-biomaterial therapeutic approach.


The relationship between glomerular IgG staining and poor prognostic findings in patients with IgA nephropathy: the data from TSN-GOLD working group.
Galactose-deficient IgA1 (Gd-IgA1) has an increased tendency to form immunocomplexes with IgG in the serum, contributing to IgAN pathogenesis by accumulating in the glomerular mesangium. Several studies showed that glomerular IgG deposition in IgAN is an important cause of mesangial proliferation and glomerular damage. This study aims to determine the association of the positivity of IgG and the intensity of IgG staining with a poor renal prognosis. A total of 943 IgAN patients were included in the study. Glomerular IgG staining negative and positive patients were compared using Oxford classification scores, histopathological evaluations, proteinuria, eGFR, albumin, blood pressures. IgG positive patients were classified as (+), (++), (+++) based on their staining intensity, and the association with the prognostic criteria was also evaluated. 81% (n = 764) of the patients were detected as IgG negative, while 19% (n = 179) were positive. Age, gender, body mass index, blood pressure, proteinuria, eGFR, uric acid values were similar in IgG positive and negative patients who underwent biopsy (p > 0.05). Intensity of glomerular IgG positivity was not found to be associated with diastolic and systolic blood pressure, urea, uric acid, age, eGFR, albumin, proteinuria (p > 0.05 for all, r = - 0.084, r = - 0.102, r = - 0.006, r = 0.062, r = 0.014, r = - 0.044, r = - 0.061, r = - 0.066, r = 0.150, respectively). There was no difference for histopathological findings between IgG (+), IgG (++), IgG (+++) groups (for all, p > 0.05). Glomerular IgG negativity and positivity detected by routine IFM in IgAN patients is not associated with poor renal prognostic risk factors.


The association between objective measures of residence and worksite neighborhood environment, and self-reported leisure-time physical activities: The Aichi Workers' Cohort Study.
The possible effects of a neighborhood's built environment on physical activity have not been studied in Asian countries as much as in Western countries. The present study cross-sectionally examined the relationship between geographic information system (GIS) measured residence and worksite neighborhood walkability, and the number of parks/green spaces and sports facilities within a 1 km radius of home and workplace, with self-reported leisure-time habitual (3-4 times per week or more) walking and moderate-to-vigorous intensity habitual exercise among local government workers aged 18 to 64 years living in an urban-suburban area of Aichi, Japan in 2013. A single-level binomial regression model was used to estimate the multivariable odds ratios (ORs) and 95% confidence intervals (95% CIs). Of the 1959 male and 884 female participants, 288 (15%) and 141 (16%) reported habitual walking, respectively, and 18% and 17% reported habitual exercise, respectively. Compared with women who resided in neighborhood with a walkability index of 4-30, those living in an area with that of 35-40 were significantly more likely to engage in leisure-time habitual exercise (multivariable OR: 1.70, 95% CI: 1.08-2.68). Marginally significant positive associations were found between leisure-time habitual exercise and the residential neighborhood's number of parks/green spaces among women, as well as the number of sports facilities among men. In conclusion, a residential neighborhood environment characterized by higher walkability may contribute to the initiation or maintenance of moderate-to-vigorous intensity leisure-time exercise among working women living in an urban-suburban area of Japan.


A cluster randomized trial of strategies to increase uptake amongst young women invited for their first cervical screen: The STRATEGIC trial.
Objectives To measure the feasibility and effectiveness of interventions to increase cervical screening uptake amongst young women. Methods A two-phase cluster randomized trial conducted in general practices in the NHS Cervical Screening Programme. In Phase 1, women in practices randomized to intervention due for their first invitation to cervical screening received a pre-invitation leaflet and, separately, access to online booking. In Phase 2, non-attenders at six months were randomized to one of: vaginal self-sample kits sent unrequested or offered; timed appointments; nurse navigator; or the choice between nurse navigator or self-sample kits. Primary outcome was uplift in intervention vs. control practices, at 3 and 12 months post invitation. Results Phase 1 randomized 20,879 women. Neither pre-invitation leaflet nor online booking increased screening uptake by three months (18.8% pre-invitation leaflet vs. 19.2% control and 17.8% online booking vs. 17.2% control). Uptake was higher amongst human papillomavirus vaccinees at three months (OR 2.07, 95% CI 1.69-2.53, p < 0.001). Phase 2 randomized 10,126 non-attenders, with 32-34 clusters for each intervention and 100 clusters as controls. Sending self-sample kits increased uptake at 12 months (OR 1.51, 95% CI 1.20-1.91, p = 0.001), as did timed appointments (OR 1.41, 95% CI 1.14-1.74, p = 0.001). The offer of a nurse navigator, a self-sample kits on request, and choice between timed appointments and nurse navigator were ineffective. Conclusions Amongst non-attenders, self-sample kits sent and timed appointments achieved an uplift in screening over the short term; longer term impact is less certain. Prior human papillomavirus vaccination was associated with increased screening uptake.


Glyphosate (Ab)sorption by Shoots and Rhizomes of Native versus Hybrid Cattail (Typha).
Wetlands in the Prairie Pothole Region of North America are integrated with farmland and contain mixtures of herbicide contaminants. Passive nonfacilitated diffusion is how most herbicides can move across plant membranes, making this perhaps an important process by which herbicide contaminants are absorbed by wetland vegetation. Prairie wetlands are dominated by native cattail (Typha latifolia) and hybrid cattail (Typha x glauca). The objective of this batch equilibrium study was to compare glyphosate absorption by the shoots and rhizomes of native versus hybrid cattails. Although it has been previously reported for some pesticides that passive diffusion is greater for rhizome than shoot components, this is the first study to demonstrate that the absorption capacity of rhizomes is species dependent, with the glyphosate absorption being significantly greater for rhizomes than shoots in case of native cattails, but with no significant differences in glyphosate absorption between rhizomes and shoots in case of hybrid cattails. Most importantly, glyphosate absorption by native rhizomes far exceeded that of the absorption occurring for hybrid rhizomes, native shoots and hybrid shoots. Glyphosate has long been used to manage invasive hybrid cattails in wetlands in North America, but hybrid cattail expansions continue to occur. Since our results showed limited glyphosate absorption by hybrid shoots and rhizomes, this lack of sorption may partially explain the poorer ability of glyphosate to control hybrid cattails in wetlands.


Exposure to triclosan augments the allergic response to ovalbumin in a mouse model of asthma.
During the last decade, there has been a remarkable and unexplained increase in the prevalence of asthma. These studies were conducted to investigate the role of dermal exposure to triclosan, an endocrine-disrupting compound, on the hypersensitivity response to ovalbumin (OVA) in a murine model of asthma. Triclosan has had widespread use in the general population as an antibacterial and antifungal agent and is commonly found in consumer products such as soaps, deodorants, toothpastes, shaving creams, mouthwashes, and cleaning supplies. For these studies, BALB/c mice were exposed dermally to concentrations of triclosan ranging from 0.75 to 3% (0.375-1.5mg/mouse/day) for 28 consecutive days. Concordantly, mice were ip injected with OVA (0.9 µg) and aluminum hydroxide (0.5mg) on days 1 and 10 and challenged with OVA (125 µg) by pharyngeal aspiration on days 19 and 27. Compared with the animals exposed to OVA alone, increased spleen weights, OVA-specific IgE, interleukin-13 cytokine levels, and numbers of lung eosinophils were demonstrated when mice were coexposed to OVA and triclosan. Statistically significant increases in OVA-specific and nonspecific airway hyperreactivity were observed for all triclosan coexposed groups compared with the vehicle and OVA controls. In these studies, exposure to triclosan alone was not demonstrated to be allergenic; however, coexposure with a known allergen resulted in enhancement of the hypersensitivity response to that allergen, suggesting that triclosan exposure may augment the allergic responses to other environmental allergens.


PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.


Quantitative in vivo evaluation of four restorative concepts for mixed Class V restorations.
This study was performed in vivo over a 6-month period to assess restorative margins in Class V restorations placed with different techniques. The margins were evaluated quantitatively under the scanning electron microscope using the replica technique. Results indicated that the sandwich technique using a glass-ionomer cement base and a composite resin restoration was not able to prevent marginal gaps in dentin. However, the experimental Gluma/Clearfil system resulted in a quality of dentinal margins not statistically significantly different from that of enamel margins. These in vivo findings substantiate in vitro results.


"How do we use the time?" - an observational study measuring the task time distribution of nurses in psychiatric care.
The nurse's primary task in psychiatric care should be to plan for the patient's care in cooperation with the patient and spend the time needed to build a relationship. Psychiatric care nurses however claim that they lack the necessary time to communicate with patients. To investigate the validity of such claims, this time-motion study aimed at identifying how nurses working at inpatient psychiatric wards distribute their time between a variety of tasks during a working day. During the period of December 2015 and February 2016, a total of 129 h and 23 min of structured observations of 12 nurses were carried out at six inpatient wards at one psychiatric clinic in southern Sweden. Time, frequency of tasks and number of interruptions were recorded and analysed using descriptive statistics. Administering drugs or medications accounted for the largest part of the measured time (17.5%) followed by indirect care (16%). Relatively little time was spent on direct care, the third largest category in the study (15.3%), while an unexpectedly high proportion of time (11.3%) was spent on ward related tasks. Nurses were also interrupted in 75% of all medication administering tasks. Nurses working in inpatient psychiatric care spend little time in direct contact with the patients and medication administration is interrupted very often. As a result, it is difficult to establish therapeutic relationships with patients. This is an area of concern for both patient safety and nurses' job satisfaction.


Chronic exposure to sublethal doses of radiation mimetic Zeocin selects for clones deficient in homologous recombination.
DNA double-strand breaks (DSBs) are highly toxic lesions leading to genome variability/instability. The balance between homologous recombination (HR) and non-homologous end-joining (NHEJ), two alternative DSB repair systems, is essential to ensure genome maintenance in mammalian cells. Here, we transfected CHO hamster cells with the pcDNA3.1/Zeo plasmid, and selected transfectants with Zeocin, a bleomycin analog which produces DSBs. Despite the presence of a Zeocin resistance gene in pcDNA3.1/Zeo, Zeocin induced 8-10 gamma-H2AX foci per cell. This shows that the Zeocin resistance gene failed to fully detoxify cells treated with Zeocin, and that during selection cells were submitted to a chronic sublethal DSB stress. Selected clones show decreases in both spontaneous and induced intrachromosomal HR. In contrast, in an in vitro assay, these clones show an increase in NHEJ products specific to the KU86 pathway. We selected cells, in the absence of pcDNA3.1/Zeo, with low and sublethal doses of Zeocin, producing a mean 8-10 gamma-H2AX foci per cell. Newly selected clones exhibited similar phenotypes: HR decrease accompanied by an increase in KU86-dependent NHEJ efficiency. Thus chronic exposure to sublethal numbers of DSBs selects cells whose HR versus NHEJ balance is altered. This may well have implications for radio- and chemotherapy, and for management of environmental hazards.


Primary care research priorities in low back pain: an update.
Survey report. To reassess an existing list of research priorities in primary care low back pain (LBP) and to develop a new research agenda. Primary care LBP researchers developed an agenda of research priorities in 1997 at an international conference. In 2009, a survey was conducted to re-evaluate the 1997 research priorities and to develop a new research agenda. Two-phase, Internet-based survey of participants in one of the LBP primary care research fora. The first phase collected information on importance, feasibility, and progress for the 1997 priorities; during this phase, the respondents were also asked to list the 5 most important current primary care-relevant LBP research questions. The second phase ranked these current research priorities. A total of 179 persons responded to the first phase, representing 30% of those surveyed. Rankings of the 1997 priorities were somewhat similar compared with 2009, although research on beliefs and expectations and improving the quality of LBP research became more important, and research on guidelines and psychosocial interventions became less important. Organizing more effective primary care for LBP, implementing best practices, and translating research to practice were ranked higher compared with 1997. Most priorities were also ranked as relatively feasible. The new agenda was similar, and included subgroup-based treatment and studies on causes and mechanisms of LBP as new top priorities. Changes in research priorities seem to reflect recent advances, new opportunities, and limitations in our ability to improve care.


Premorbid cognitive testing predicts the onset of dementia and Alzheimer's disease better than and independently of APOE genotype.
To determine whether a cognitive test package can predict the onset of dementia up to 11 years later, and the extent to which this prediction is independent of that provided by APOE genotype. Prospective cohort study based on 54 general practices in the UK; 657 survivors of the 1088 participants in the MRC treatment trial of hypertension in older adults were followed for up to 11 years; 370 participants (57% of survivors) were traced, screened for dementia, and genotyped for APOE in 1994. Baseline assessments included trail making test A, paired associated learning test, Raven's progressive matrices, and national adult reading test. At follow up, both mini-mental state examination and CAMCOG were used. Outcome measures were DSM-IIIR dementia and NINCDS-ADRDA possible and probable Alzheimer's disease. All the cognitive tests completed in 1983 predicted onset of dementia and Alzheimer's disease up to 11 years later, as did APOE genotype. Cognitive test performance was not associated with APOE genotype. Addition of cognitive tests increased the area under the ROC curve for the prediction of Alzheimer's disease provided by age, family history, and APOE genotype (0.81 v 0.69, p = 0.048); addition of APOE genotype did not increase the area under the ROC curve for the prediction provided by age, family history, and cognitive tests (0.81 v 0.77, p = 0.28). Simple tests of cognitive ability provide useful predictive information up to a decade before the onset of dementia. The predictive information provided is independent of, but not enhanced by, the addition of APOE genotype.


Ten considerations for effectively managing the COVID-19 transition.
Governments around the world have implemented measures to manage the transmission of coronavirus disease 2019 (COVID-19). While the majority of these measures are proving effective, they have a high social and economic cost, and response strategies are being adjusted. The World Health Organization (WHO) recommends that communities should have a voice, be informed and engaged, and participate in this transition phase. We propose ten considerations to support this principle: (1) implement a phased approach to a 'new normal'; (2) balance individual rights with the social good; (3) prioritise people at highest risk of negative consequences; (4) provide special support for healthcare workers and care staff; (5) build, strengthen and maintain trust; (6) enlist existing social norms and foster healthy new norms; (7) increase resilience and self-efficacy; (8) use clear and positive language; (9) anticipate and manage misinformation; and (10) engage with media outlets. The transition phase should also be informed by real-time data according to which governmental responses should be updated.


Effect of subconjunctivally injected, liposome-bound, low-molecular-weight heparin on the absorption rate of subconjunctival hemorrhage in rabbits.
To investigate the effect of subconjunctival injection of liposome-bound, low-molecular-weight heparin (LMWH) on the absorption rate of subconjunctival hemorrhages. Subconjunctival hemorrhages were induced in both eyes of 30 rabbits by the subconjunctival injection of 0.1 mL of autologous blood from auricular marginal veins. After 8 hours, randomized subconjunctival injections of one of three materials were made: 5 IU/mL liposome-bound LMWH (0.1 mL) in 18 eyes (group A), only liposomes (0.1 mL) in 14 eyes (group B), the free form of LMWH (5 IU/mL, 0.1 mL) in 14 eyes (group C), or no injection in 14 eyes (group D). Subconjunctival hemorrhages were photographed with a digital camera at 8, 24, 48, 72, 96, and 120 hours after induction of subconjunctival hemorrhages, sized with an image analyzer, and compared between groups. Subconjunctival hemorrhages were absorbed faster in group A (liposome-bound LMWH injected) than in with group B (liposome injected). Comparison of groups A and C (free LMWH injected) showed statistical differences in the absorption rates at 96 and 120 hours except at 24, 48, and 72 hours. The mean elapsed time for the complete resorption of subconjunctival hemorrhages was shortest in group A among four groups, whereas group B and the control showed no significant differences. The ocular and systemic absorption of LMWH were significantly lower after injection of the liposome-bound than the free form. The subconjunctival injection of liposome-bound LMWH appears to enhance subconjunctival hemorrhage absorption in rabbits.


A glimpse into the biogeography, seasonality, and ecological functions of arctic marine Oomycota.
High-latitude environments are warming, leading to changes in biological diversity patterns of taxa. Oomycota are a group of fungal-like organisms that comprise a major clade of eukaryotic life and are parasites of fish, agricultural crops, and algae. The diversity, functionality, and distribution of these organisms are essentially unknown in the Arctic marine environment. Thus, it was our aim to conduct a first screening, using a functional gene assay and high-throughput sequencing of two gene regions within the 18S rRNA locus to examine the diversity, richness, and phylogeny of marine Oomycota within Arctic sediment, seawater, and sea ice. We detected Oomycota at every site sampled and identified regionally localized taxa, as well as taxa that existed in both Alaska and Svalbard. While the recently described diatom parasite Miracula helgolandica made up about 50% of the oomycete reads found, many lineages were observed that could not be assigned to known species, including several that clustered with another recently described diatom parasite, Olpidiopsis drebesii. Across the Arctic, Oomycota comprised a maximum of 6% of the entire eukaryotic microbial community in Barrow, Alaska May sediment and 10% in sea ice near the Svalbard archipelago. We found Arctic marine Oomycota encode numerous genes involved in parasitism and carbon cycling processes. Ultimately, these data suggest that Arctic marine Oomycota are a reservoir of uncharacterized biodiversity, the majority of which are probably parasites of diatoms, while others might cryptically cycle carbon or interface other unknown ecological processes. As the Arctic continues to warm, lower-latitude Oomycota might migrate into the Arctic Ocean and parasitize non-coevolved hosts, leading to incalculable shifts in the primary producer community.


Evaluation of a curcumin-containing mucoadhesive film for periodontal postsurgical pain control.
Management of pain and discomfort is important to make the postoperative period as pleasant as possible. Nonsteroidal anti-inflammatory drugs are traditionally prescribed; however, they are associated with numerous side effects. As a result, nutraceuticals such as curcumin are widely used for its well-known safety and medicinal values. Hence, the aim of this study is to evaluate the efficacy of a curcumin mucoadhesive film for postsurgical pain control. This was a split-mouth study, consisting of 15 systemically healthy patients with 30 sites, who were randomly allocated into test (curcumin mucoadhesive film) and control (placebo mucoadhesive film) groups using coin toss method. A questionnaire was given to patients to evaluate the postoperative pain and swelling and the number of rescue medications taken. Statistical analyses used were Friedman test, Wilcoxon signed-rank test, and McNemar's test. No adverse effects were reported and healing was uneventful in all patients. The Numerical rating scale pain score showed significantly lesser pain at 1, 2, 3, 4, 5, and 24 h in the test group. Significantly more number of analgesics was consumed in total in the control group than that in the test group. Within the limitations of this study, it may be concluded that curcumin mucoadhesive film showed promising results in reducing postoperative pain and swelling over a period of 1 week, hence showing its analgesic effect after periodontal surgeries.


Processing emotion information from both the face and body: an eye-movement study.
This study examined the perception of emotional expressions, focusing on the face and the body. Photographs of four actors expressing happiness, sadness, anger, and fear were presented in congruent (e.g., happy face with happy body) and incongruent (e.g., happy face with fearful body) combinations. Participants selected an emotional label using a four-option categorisation task. Reaction times and accuracy for the categorisation judgement, and eye movements were the dependent variables. Two regions of interest were examined: face and body. Results showed better accuracy and faster reaction times for congruent images compared to incongruent images. Eye movements showed an interaction in which there were more fixations and longer dwell times to the face and fewer fixations and shorter dwell times to the body with incongruent images. Thus, conflicting information produced a marked effect on information processing in which participants focused to a greater extent on the face compared to the body.


[Air pollution and pediatric hospital admissions due to respiratory diseases in Cubatão, São Paulo State, Brazil, from 1997 to 2004].
The aim of this study was to evaluate the effects of air pollutants and their lag structures in relation to respiratory morbidity among children and adolescents in the city of Cubatão, São Paulo State, Brazil, from 1997 to 2004. An ecological time-series study was performed, analyzing respiratory hospital admissions of children and adolescents in National Health System hospitals in Cubatão. Generalized linear Poisson regression models were used to control for seasonality, temperature, humidity, and short-term trends. PM10 and ozone were significantly associated with respiratory hospital admissions. Among children, inter-quartile range increases in the PM10 7-day moving average (56.5µg/m³) and in the ozone 5-day moving average (46.7µg/m³) led to increases of 9.6% (95%CI: 3.0%-16.1%) and 2.4% (95%CI: 0.1%-4.7%) in respiratory hospital admissions, respectively. Efforts to reduce air pollutants need to be adopted to minimize the adverse effects on children and adolescents in Cubatão.


Multidisciplinary approach to expansion thoracoplasty for congenital spinal deformity: a preliminary report.
In children with congenital chest wall deformities, the vertical expandable prosthetic titanium Rib (VEPTR) has recently been developed to move the emphasis away from corrective spinal fusion, to expanding the deformed hemithorax. The aim of this paper is to demonstrate the need for paediatric surgeons in what is primarily an orthopaedic procedure. All patients less than 5 years old who had primary congenital scoliosis with poor respiratory function and were treated by VEPTR at our institution in conjunction with the spinal orthopaedic surgeons were reviewed. All 6 cases required rib exposure and thoracostomy by a paediatric surgeon. One required exposure of the ribs only, 3 required an extrapleural thoracotomy and 2 required intrapleural thoracotomy with a patch repair of the rib space. None of the patients required blood transfusion and there were no early complications. All patients showed radiological improvement of their spinal and thoracic deformity as well as improvement in their respiratory function. Paediatric surgeons play an important role in the thoracic exposure required for this orthopaedic procedure. The benefit of a multidisciplinary approach is highlighted in this paper. The VEPTR implant may replace major spinal fusion surgery in this challenging group of patients.


Preparation of microbubble suspensions by co-axial electrohydrodynamic atomization.
In this paper we report a novel method, based on co-axial electrohydrodynamic jetting, for the preparation of microbubble suspensions containing bubbles <10 microm in size and having a narrow size distribution. No selective filtration is necessary and the suspensions are produced directly by the process. To demonstrate the method, glycerol was used as the liquid medium, flowing in the outer needle of the co-axial twin needle arrangement and undergoing electrohydrodynamic atomization in the stable cone-jet mode while air flowed through the inner needle at the same time. At zero applied voltage a hollow stream of liquid flowed from the outer needle. When the applied voltage was increased, eventually the hollow stream became a stable cone-jet and emitted a microthread of bubbles, which were collected in a container of glycerol to obtain microbubble suspensions. The size of the microbubbles was measured via optical microscopy and laser diffractometry. Several microbubble suspensions were prepared and characterised and the size distribution was found to be critically dependent on the ratio (n) of flow rates of liquid/air and, in particular the flow rate of the air. At n=1.5, with the flow rate of air set at approximately 1.7 microl/s, a microbubble suspension containing bubbles in the size range 2-8 microm was obtained.


Chloride channels in stellate cells are essential for uniquely high secretion rates in neuropeptide-stimulated Drosophila diuresis.
Epithelia frequently segregate transport processes to specific cell types, presumably for improved efficiency and control. The molecular players underlying this functional specialization are of particular interest. In Drosophila, the renal (Malpighian) tubule displays the highest per-cell transport rates known and has two main secretory cell types, principal and stellate. Electrogenic cation transport is known to reside in the principal cells, whereas stellate cells control the anion conductance, but by an as-yet-undefined route. Here, we resolve this issue by showing that a plasma membrane chloride channel, encoded by ClC-a, is exclusively expressed in the stellate cell and is required for Drosophila kinin-mediated induction of diuresis and chloride shunt conductance, evidenced by chloride ion movement through the stellate cells, leading to depolarization of the transepithelial potential. By contrast, ClC-a knockdown had no impact on resting secretion levels. Knockdown of a second CLC gene showing highly abundant expression in adult Malpighian tubules, ClC-c, did not impact depolarization of transepithelial potential after kinin stimulation. Therefore, the diuretic action of kinin in Drosophila can be explained by an increase in ClC-a-mediated chloride conductance, over and above a resting fluid transport level that relies on other (ClC-a-independent) mechanisms or routes. This key segregation of cation and anion transport could explain the extraordinary fluid transport rates displayed by some epithelia.


Associations of chronic obstructive pulmonary disease with all-cause mortality in Blacks and Whites: the atherosclerosis risk in communities (ARIC) study.
To determine the burden of chronic obstructive pulmonary disease (COPD) on all-cause mortality in Blacks and Whites from four US communities. We determined prospectively the risk of death through December 2004 in relation to baseline (1987-1989) COPD status in 10,333 Black and White participants of the Atherosclerosis Risk in Communities (ARIC) study. Over a mean follow-up of 15 years (maximum 18 years), 462 deaths occurred in Blacks and 1221 deaths occurred in Whites. Hazard ratios for all-cause mortality among Blacks and Whites were similar (hazard ratio [HR] = 1.74 in Blacks and HR = 1.59 in Whites), indicating a 59%-74% greater risk of mortality for those with COPD. However, for both those with and without COPD, crude death rates were approximately double in Blacks compared to Whites. Our findings suggest that given COPD, Blacks and Whites have the same proportionate increase in mortality and that the difference in death rates between Blacks and Whites cannot be explained by COPD status. The public health burden of COPD is enormous, and strategies to reduce COPD and smoking could have a large impact on total mortality rates of both Blacks and Whites.


Microemulsions are highly effective anti-biofilm agents.
The demonstration of the antibiofilm effects of pharmaceutical microemulsions. Microemulsions were prepared as physically stable oil/water systems. Previous work by this group has shown that microemulsions are highly effective antimembrane agents that result in rapid losses of viability in planktonic populations of Pseudomonas aeruginosa and Staphylococcus aureus. In this experiment a microemulsion preparation was used upon established biofilm cultures of Ps. aeruginosa PA01 for a period of 4 h. The planktonic MIC of sodium pyrithione and the planktonic and biofilm MICs of cetrimide were used as positive controls and a biofilm was exposed to a volume of normal sterile saline as a treatment (negative) control. Results indicate three log-cycle reductions in viability within the microemulsion treated biofilm, as compared to those observed in control treatments of similar biofilms (one log-cycle reduction in viabilities). The results indicate that the microemulsions are highly effective antibiofilm agents. This study suggests that microemulsions may have a role in the treatment of industrial and environmental biofilms.


Experimentally Determined Subsolidus Metal-Olivine Element Partitioning with Applications to Pallasites.
Pallasite meteorites, which consist primarily of olivine and metal, may be remnants of disrupted core-mantle boundaries of differentiated asteroids or planetesimals. The early thermal histories of pallasites are potentially recorded by minor- and trace-element zonation in olivine. However, constraining this history requires knowledge of element behavior under the conditions of pallasite formation, which is lacking for many of the main elements of interest (e.g., Co, Cr, Mn). In this study, we experimentally determined metal/olivine partition coefficients for Fe, Ni, Co, Cr, and Mn in a pallasite analogue at subsolidus temperatures. Metal/olivine partition coefficients (KM ) increase in the order KMn < KCr < 1 < KFe < KCo < KNi , with five orders of magnitude separating KMn from KNi . Transition metals also become more siderophile with increasing experimental temperature (900 to 1550°C). The experiments incidentally produced diffusion profiles in olivine for these elements; Our results suggest they diffuse through olivine at similar rates. Core compositions of pallasite olivines are consistent with high-temperature equilibration with FeNi-metal. Olivine zonation toward crystal rims varies significantly for the investigated transition metals. We suggest rim zonation results from partial re-equilibration during late stage crystallization of minor phases (e.g., chromite, phosphates). This re- equilibration occurred over short timescales relative to overall pallasite cooling, likely tied to initial cooling rates on the order of 100-300°C/Myr.


Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests.
Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 microg/dL in all ALF-WD patients measured (13/16), but were also elevated in non-WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.


Secretory activity is rapidly induced in stigmatic papillae by compatible pollen, but inhibited for self-incompatible pollen in the Brassicaceae.
[In the Brassicaceae, targeted exocytosis to the stigmatic papillar plasma membrane under the compatible pollen grain is hypothesized to be essential for pollen hydration and pollen tube penetration. In contrast, polarized secretion is proposed to be inhibited in the stigmatic papillae during the rejection of self-incompatible pollen. Using transmission electron microscopy (TEM), we performed a detailed time-course of post-pollination events to view the cytological responses of the stigmatic papillae to compatible and self-incompatible pollinations. For compatible pollinations in Arabidopsis thaliana and Arabidopsis lyrata, vesicle secretion was observed at the stigmatic papillar plasma membrane under the pollen grain while Brassica napus stigmatic papillae appeared to use multivesicular bodies (MVBs) for secretion. Exo70A1, a component of the exocyst complex, has been previously implicated in the compatible pollen responses, and disruption of Exo70A1 in both A. thaliana and B. napus resulted in a loss of secretory vesicles/MVBs at the stigmatic papillar plasma membrane. Similarly, for self-incompatible pollinations, secretory vesicles/MVBs were absent from the stigmatic papillar plasma membrane in A. lyrata and B. napus; and furthermore, autophagy appeared to be induced to direct vesicles/MVBs to the vacuole for degradation. Thus, these findings support a model where the basal pollen recognition pathway in the stigmatic papilla promotes exocytosis to accept compatible pollen, and the basal pollen recognition pathway is overridden by the self-incompatibility pathway to prevent exocytosis and reject self-pollen.


Abundance and distribution of iron on the moon.
The abundance and distribution of iron on the moon is derived from a near-global data set from Clementine. The determined iron content of the lunar highlands crust ( approximately 3 percent iron by weight) supports the hypothesis that much of the lunar crust was derived from a magma ocean. The iron content of lower crustal material exposed by the South Pole-Aitken impact basin on the lunar farside is higher ( approximately 7 to 8 percent by weight) and consistent with a basaltic composition. This composition supports earlier evidence that the lunar crust becomes more mafic with depth. The data also suggest that the bulk composition of the moon differs from that of the Earth's mantle. This difference excludes models for lunar origin that require the Earth and moon to have the same compositions, such as fission and coaccretion, and favors giant impact and capture.


Orthopantomography and Cone-Beam Computed Tomography for the Relation of Inferior Alveolar Nerve to the Impacted Mandibular Third Molars.
Relation of inferior alveolar nerve to the impacted mandibular third molars (IMTMs). The aim of this study was to assess the reliability of seven specific radiographic signs of mandibular third molar root that are observed on orthopantomography (OPG) and to predict the proximity and the absence of corticalization between the mandibular canal and IMTM root on cone-beam computed tomography (CBCT) images. The present study was conducted in the Department of Oral and Maxillofacial Surgery, Raja Rajeswari Dental College and Hospital. Data set of 30 panoramic images was retrieved between the year of 2015 and 2016 indicated for extraction of lower third molars. The sample consisted of 30 individuals, who underwent preoperative radiographic evaluation before the extraction of impacted mandibular third molars (IMTM). Patients aged above 18 years with any of the seven specific signs observed on the panoramic radiograph which includes darkening, deflection, narrowing of roots, bifid root apex, diversion, narrowing of canal and interruption in the white line of the canal were included in the study. If any of the above mentioned seven specific sign were present, the patient was subjected to CBCT. On the CBCT images, the canal was traced in three planes. The acquired images were assessed for the presence or absence of corticalization. Descriptive and inferential statistical analyses were used. Proportions were compared using the Chi-square test and Student's t-test. Among the 4 subjects, diagnosed with an absence of corticalization, patients with isolated darkening of root P = 0.001 and patients with isolated interruption in white line P = 0.69. Patients with darkening of root in association with interruption in white lines on OPG showed the absence of corticalization on CBCT findings P = 0.001, respectively. This study showed the poor reliability of radiographic signs seen on OPG on predicting the proximity of third mandibular root with mandibular canal related to CBCT finding. Four were diagnosed with the absence of corticalization in CBCT findings.


The genetics of a small chromosome region of Drosophila melanogaster containing the structural gene for alcohol dehydrogenase. IV: scutoid, an antimorphic mutation.
Exchange mapping locates the dominant mutation Scutoid to the right of Adh on chromosome arm 2L of D. melanogaster. However, deletion mapping indicates that Sco is to the left of Adh. The phenotype of Sco is sensitive to mutation, or deletion, of noc+ and of three genes, el, l(2)br22, and l(2)br29 mapping immediately distal to noc. The four contiguous loci, el, l(2)br22, l(2) br29 and noc, although separable by deletion end points, interact, because certain (or all) alleles of these four loci show partial failure of complementation, or even negative complementation. The simplest hypothesis is that Sco is a small reciprocal transposition, the genes noc, osp, and Adh exchanging places with three genes normally mapping proximal to them: l(2)br34, 1(2)br35 and rd. The Sco phenotype is thought to result from a position effect at the newly created noc/l(2)br28 junction.


Using Speed of Sound Imaging to Characterize Breast Density.
A population of 165 women with negative mammographic screens also received an ultrasound tomography (UST) examination at the Karmanos Cancer Institute in Detroit, MI. Standard statistical techniques were employed to measure the associations between the various mammographic- and UST-related density measures and various participant characteristics such as age, weight and height. The mammographic percent density (MPD) was found to have similar strength associations with UST mean sound speed (Spearman coefficient, rs = 0.722, p < 0.001) and UST median sound speed (rs = 0.737, p < 0.001). Both were stronger than the associations between MPD with two separate measures of UST percent density, a k-means (rs = 0.568, p < 0.001) or a threshold (rs = 0.715, p < 0.001) measure. Segmentation of the UST sound speed images into dense and non-dense volumes showed weak to moderate associations with the mammographically equivalent measures. Relationships were found to be inversely and weakly associated between age and the UST mean sound speed (rs = -0.239, p = 0.002), UST median sound speed (rs = -0.226, p = 0.004) and MPD (rs = -0.204, p = 0.008). Relationships were found to be inversely and moderately associated between body mass index (BMI) and the UST mean sound speed (rs = -0.429, p < 0.001), UST median sound speed (rs = -0.447, p < 0.001) and MPD (rs = -0.489, p < 0.001). The results confirm and strengthen findings presented in previous work indicating that UST sound speed imaging yields viable markers of breast density in a manner consistent with mammography, the current clinical standard. These results lay the groundwork for further studies to assess the role of sound speed imaging in risk prediction.


Insights into virus evolution and membrane biogenesis from the structure of the marine lipid-containing bacteriophage PM2.
Recent, primarily structural observations indicate that related viruses, harboring no sequence similarity, infect hosts of different domains of life. One such clade of viruses, defined by common capsid architecture and coat protein fold, is the so-called PRD1-adenovirus lineage. Here we report the structure of the marine lipid-containing bacteriophage PM2 determined by crystallographic analyses of the entire approximately 45 MDa virion and of the outer coat proteins P1 and P2, revealing PM2 to be a primeval member of the PRD1-adenovirus lineage with an icosahedral shell and canonical double beta barrel major coat protein. The view of the lipid bilayer, richly decorated with membrane proteins, constitutes a rare visualization of an in vivo membrane. The viral membrane proteins P3 and P6 are organized into a lattice, suggesting a possible assembly pathway to produce the mature virus.


First Report of Xylella fastidiosa Associated with Leaf Scorch in Black Oak in Washington, D.C.
Bacterial leaf scorch caused by Xylella fastidiosa has been reported in 17 species of oak including bur, pin, red, scarlet, shingle, and white oaks (3). In September 2002, a leaf scorch symptom characterized by marginal necrosis of leaves bordered by a darker brown band was observed in a mature black oak (Quercus velutina Lam.) at the U.S. National Arboretum in Washington, D.C. The leaf petiole of the black oak was processed in general extraction buffer (Agdia, Inc., Elkhart, IN) contained in a FastDNA lysing matrix tube using the FastPrep FP120 instrument (Qbiogene, Inc., Carlsbad, CA) (1). The leaf petiole extract reacted with an antiserum specific for X. fastidiosa (Agadia, Inc.) in an enzyme-linked immunosorbent assay (ELISA). A slow-growing bacterium was cultured from leaf petioles of the affected black oak tree by soaking the surface-sterilized, finely cut leaf petioles in sterile water for 30 min, followed by spreading the bacterial suspension on periwinkle wilt plates (1). When the cultured bacterium was subjected to polymerase chain reaction (PCR) with primers specific for X. fastidiosa (2), a 472-bp PCR product was detected. The PCR product was confirmed to be the predicted X. fastidiosa product by sequencing and sequence comparison with the reported genomic sequence of X. fastidiosa. ELISA and bacterial isolation from leaf petioles of a nearby symptomless white oak (Q. alba L.) tree were negative. To our knowledge, this is the first report of X. fastidiosa associated with leaf scorch in black oak in the United States, expanding the host range of the bacterium in economically important landscape tree species. References: (1) Q. Huang and J. L. Sherald. Curr. Microbiol. 48:73, 2004. (2) M. R. Pooler and J. S. Hartung. Curr. Microbiol. 31:377, 1995. (3) J. L. Sherald. Xylella fastidiosa, A bacterial pathogen of landscape trees. Page 191 in: Shade Tree Wilt Diseases, C. L. Ash, ed. The American Phytopathological Society, 2001.


Estimating the number of animals: a rapid method for unidentified individuals.
A proposed model yields the density of a mobile population from quick, cursory surveys in which the observer identifies none of the animals. When the spaces on which animals were seen are successively removed, the decline in the counts permits estimation of the average probability of seeing a given animal. The method showed promise in initial trials.


Hildreth's test is a reliable clinical sign for the diagnosis of glomus tumours.
Hildreth's test is a clinical test for the diagnosis of glomus tumours. It is positive if there is a reduction in pain and tenderness on exsanguination and ischaemia of the affected part. This study assessed Hildreth's test, and found 92% sensitivity and 91% specificity with a positive predictive value of 92% and a negative predictive value of 91%.


Allopurinol reduces cardiovascular risks and improves renal function in pre-dialysis chronic kidney disease patients with hyperuricemia.
To determine the effect of hyperuricemia and allopurinol therapy on renal functions in chronic kidney disease (CKD) stage 3-4, we studied 96 patients in stage 3-4 CKD (57% male, age 65.3 ± 12.4 years). The mean estimated glomerular filtration rate (GFR) was 44.62 ± 14.38 iriL/ min/1.73 m 2 . The study patients were divided into non-allopurinol users (n = 47) and those using allopurinol (n = 49) in the last 12 months. Serum uric acid (UA) and C-reactive protein levels decreased after allopurinol therapy (P = 0.00 and P = 0.04, respectively), but no change was observed in the control group during the study period. In the allopurinol group, the mean GFR increased 3.3 ±1.2 mL/min/1.73 m 2 /year, while it decreased 1.3 ± 0.6 mL/min/1.73 m 2 in the control group during the follow-up period (P = 0.04); the patients in the allopurinol group exhibited lower levels of serum potassium, serum low-density lipoprotein (LDL) and renal resistance index (RRI) (P-values were <0.05). The patients with stable renal functions or GFR change <10% (n = 25) at the end of 12 months had significantly lower LDL and RRI values and more allopurinol users than the group with decreasing GFR (74% vs. 48%, P <0.05). In the regression analysis, UA and RRI were found as independent variables (r 2 = 0.68, P <0.01; r 2 = 0.25, P <0.01) that affected loss of renal function. We conclude that our study suggests a role for allopurinol, an effective agent in lowering serum UA levels, as a reliable therapeutic option in controlling renal progression in pre-dialysis CKD patients.


Unfolding grain size effects in barium titanate ferroelectric ceramics.
Grain size effects on the physical properties of polycrystalline ferroelectrics have been extensively studied for decades; however there are still major controversies regarding the dependence of the piezoelectric and ferroelectric properties on the grain size. Dense BaTiO3 ceramics with different grain sizes were fabricated by either conventional sintering or spark plasma sintering using micro- and nano-sized powders. The results show that the grain size effect on the dielectric permittivity is nearly independent of the sintering method and starting powder used. A peak in the permittivity is observed in all the ceramics with a grain size near 1 μm and can be attributed to a maximum domain wall density and mobility. The piezoelectric coefficient d33 and remnant polarization Pr show diverse grain size effects depending on the particle size of the starting powder and sintering temperature. This suggests that besides domain wall density, other factors such as back fields and point defects, which influence the domain wall mobility, could be responsible for the different grain size dependence observed in the dielectric and piezoelectric/ferroelectric properties. In cases where point defects are not the dominant contributor, the piezoelectric constant d33 and the remnant polarization Pr increase with increasing grain size.


Hypoxia reduces the hypothalamic thermogenic threshold and thermosensitivity.
Hypoxia is well known to reduce the body temperature (T(b)) of mammals, although the neural origins of this response remain uncertain. Short-term hypoxic exposure causes a reduction in the lower critical temperature of the thermal neutral zone and a reduction in whole body thermal conductance of rodents, providing indirect support that hypoxia lowers T(b) in a regulated manner. In this study, we examined directly the potential for changes in central thermosensitivity to evoke the hypoxic metabolic response by heating and cooling the preoptic area of the hypothalamus (the area which integrates thermoreceptor input and regulates thermoeffector outputs) using chronic, indwelling thermodes in ground squirrels during normoxia and hypoxia (7, 10 and 12% O(2)). We found that the threshold hypothalamic temperature for the metabolic response to cooling (T(th)) of approximately 38 degrees C in normoxia was proportionately reduced in hypoxia (down to 28-31 degrees C at 7% O(2)) and that the metabolic thermosensitivity (alpha; the change in metabolic rate for any given change in hypothalamic temperature below the lower critical temperature) was comparatively reduced by 5 to 9 times. This provides strong support for the hypothesis that the fall in temperature that occurs during hypoxia is the result of a reduction in the activation of thermogenic mechanisms. The decrease in the central thermosensitivity in hypoxia, however, appears to be a critical factor in the alteration of mammalian T(b). We suggest, therefore, that an altered central thermosensitivity may provide a proximate explanation of how low oxygen and similar stressors reduce normal fluctuations in T(b) (i.e. circadian), in addition to the depression in regulated T(b).


A national analysis of dental waiting lists and point-in-time geographic access to subsidised dental care: can geographic access be improved by offering public dental care through private dental clinics?
Australia is one of the least densely populated countries in the world, with a population concentrated on or around coastal areas. Up to 33% of the Australian population are likely to have untreated dental decay, while people with inadequate dentition (fewer than 21 teeth) account for up to 34% of Australian adults. Historically, inadequate access to public dental care has resulted in long waiting lists, received much media coverage and been the subject of a new federal and state initiative. The objective of this research was to gauge the potential for reducing the national dental waiting list through geographical advantage, which could arise from subcontracting the delivery of subsidised dental care to the existing network of private dental clinics across Australia. Eligible population data were collected from the Australian Bureau of Statistics website. Waiting list data from across Australia were collected from publicly available sources and confirmed through direct communication with each individual state or territory dental health body. Quantum geographic information system software was used to map distribution of the eligible population across Australia by statistical area, and to plot locations of government and private dental clinics. Catchment areas of 5 km for metropolitan clinics and 5 km and 50 km for rural clinics were defined. The number of people on the waiting list and those eligible for subsidised dental care covered by each of the catchment areas was calculated. Percentage of the eligible population and those on the waiting list that could benefit from the potential improvement in geographic access was ascertained for metropolitan and rural residents. Fifty three percent of people on the waiting list resided within metropolitan areas. Rural and remote residents made up 47% of the population waiting to receive care. The utilisation of both government and private dental clinics for the delivery of subsidised dental care to the eligible population has the potential to improve geographic access for up to 25% of those residing within metropolitan areas and up to 59% for eligible country residents. This research finds that utilisation of the existing network of private dental practices across Australia for delivery of subsidised dental care could dramatically increase geographic reach, reduce waiting lists, and possibly make good oral health a more realistic goal to achieve for the economically disadvantaged members of the community. In addition, this approach has the potential to improve service availability in rural and remote areas for entire communities where existing socioeconomic dynamics do not foster new practice start-up.


Stretch-induced nitric oxide modulates mechanical properties of skeletal muscle cells.
In this study, we examined the hypothesis that stretch-induced (nitric oxide) NO modulates the mechanical properties of skeletal muscles by increasing accumulation of protein levels of talin and vinculin and by inhibiting calpain-induced proteolysis, thereby stabilizing the focal contacts and the cytoskeleton. Differentiating C(2)C(12) myotubes were subjected to a single 10% step stretch for 0-4 days. The apparent elastic modulus of the cells, E(app), was subsequently determined by atomic force microscopy. Static stretch led to significant increases (P < 0.01) in E(app) beginning at 2 days. These increases were correlated with increases in NO activity and neuronal NO synthase (nNOS) protein expression. Expression of talin was upregulated throughout, whereas expression of vinculin was significantly increased only on days 3 and 4. Addition of the NO donor l-arginine onto stretched cells further enhanced E(app), NOS activity, and nNOS expression, whereas the presence of the NO inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) reversed the effects of mechanical stimulation and of l-arginine. Overall, viscous dissipation, as determined by the value of hysteresis, was not significantly altered. For assessment of the role of vinculin and talin stability, cells treated with l-NAME showed a significant decrease in E(app), whereas addition of a calpain inhibitor abolished the effect. Thus our results show that NO inhibition of calpain-initiated cleavage of cytoskeleton proteins was correlated with the changes in E(app). Together, our data suggest that NO modulates the mechanical behavior of skeletal muscle cells through the combined action of increased talin and vinculin levels and a decrease in calpain-mediated talin proteolysis.


Variations in Antibiotic Use and Sepsis Management in Neonatal Intensive Care Units: A European Survey.
Management of neonatal sepsis and the use of antimicrobials have an important impact on morbidity and mortality. However, there is no recent background on which antibiotic regimens are used in different European neonatal intensive care units (NICUs). Our study aimed to describe the use of antibiotics and other aspects of early- and late-onset sepsis (EOS and LOS, respectively) management by European NICUs. We conducted an online survey among NICUs throughout Europe to collect information about antibiotic stewardship, antibiotic regimens, and general aspects of managing neonatal infections. NICUs from up to 38 European countries responded, with 271 valid responses. Most units had written clinical guidelines for EOS (92.2%) and LOS (81.1%) management. For EOS, ampicillin, penicillin, gentamicin, and amikacin were the most commonly used antibiotics. Analysis of the combinations of EOS regimens showed that the most frequently used was ampicillin plus gentamicin (54.6%). For LOS, the most frequently used antibiotics were vancomycin (52.4%), gentamicin (33.9%), cefotaxime (28%), and meropenem (15.5%). Other aspects of the general management of sepsis have also been analyzed. The management of neonatal sepsis in European NICUs is diverse. There was high self-reported adherence to the local clinical guidelines. There was homogeneity in the combination of antibiotics in EOS but less in LOS.


A mathematical model of mucilage expansion in myxospermous seeds of Capsella bursa-pastoris (shepherd's purse).
Myxospermy is a term which describes the ability of a seed to produce mucilage upon hydration. The mucilage is mainly comprised of plant cell-wall polysaccharides which are deposited during development of those cells that comprise the seed coat (testa). Myxospermy is more prevalent among those plant species adapted to surviving on arid sandy soils, though its significance in determining the ecological fitness of plants is unclear. In this study, the first mathematical model of myxospermous seed mucilage expansion is presented based on seeds of the model plant species Capsella bursa-pastoris (shepherd's purse). The structures underpinning the expansion process were described using light, electron and time-lapse confocal micrographs. The data and experimental observations were used to create a mathematical model of myxospermous seed mucilage expansion based on diffusion equations. The mucilage expansion was rapid, taking 5 s, during which the cell mucilage volume increased 75-fold. At the level of the seed, this represented a 6-fold increase in seed volume and a 2·5-fold increase in seed surface area. These increases were shown to be a function of water uptake (16 g water g(-1) mucilage dry weight), and relaxation of the polymers which comprised the mucilage. In addition, the osmotic pressure of the seed mucilage, estimated by assessing the mucilage expansion of seeds hydrated in solutions of varying osmotic pressure, was -0·54 MPa (equivalent to 0·11 M or 6·6 g L(-1) NaCl). The results showed that the mucilage may be characterized as hydrogel and seed-mucilage expansion may be modelled using the diffusion equation described. The potential of myxospermous seeds to affect the ecological services provided by soil is discussed briefly.


Noradrenergic enhancement of amygdala responses to fear.
Multiple lines of evidence implicate the basolateral amygdala (BLA) and the noradrenergic (norepinephrine, NE) system in responding to stressful stimuli such as fear signals, suggesting hyperfunction of both in the development of stress-related pathologies including anxiety disorders. However, no causative link between elevated NE neurotransmission and BLA hyperresponsiveness to fear signals has been established to date in humans. To determine whether or not increased noradrenergic tone enhances BLA responses to fear signals, we used functional magnetic resonance imaging (fMRI) and a strategy of pharmacologically potentiating NE neurotransmission in healthy volunteers. 18 subjects were scanned two times on a facial emotion paradigm and given either a single-dose placebo or 4 mg of the selective NE reuptake inhibitor reboxetine 2 h prior to an fMRI session. We found that reboxetine induced an amygdala response bias towards fear signals that did not exist at placebo baseline. This pharmacological effect was probabilistically mapped to the BLA. Extrapolation of our data to conditions of traumatic stress suggests that disinhibited endogenous NE signaling could serve as a crucial etiological contributor to post-traumatic stress disorder (PTSD) by eliciting exaggerated BLA responses to fear signals.


[Investigating language acquisition disorders based on the complaints].
To investigate complaints commonly reported by parents of children with language disorders. In addition, we have analyzed the conditions of verbal production and comprehension of these children. The sample comprised 55 children of both genders with ages between 2 and 12 years old. The complaints reported by their families at the beginning of therapeutic intervention were analyzed and subdivided, considering deficits on verbal production, verbal comprehension and both (mixed comprehension and production deficits). Subsequently, we analyzed the performance of these children in verbal comprehension and production tests, in phonological, semantic, grammatical and pragmatic levels. By analyzing the performance of children whose families complained about verbal production (82.6%), it was found that 55.2% of them also presented verbal comprehension deficits. Verbal production deficits occurred at phonological (97.3%), semantic (76.3%), grammatical (78.9%) and pragmatic (5.2%) levels. Although complaints regarding verbal production deficits are more common, verbal comprehension deficits are also evident in children with language disorders. These findings evidence the importance of careful evaluation based on the complaints presented by the families.


Diagnostic accuracy of the American Diabetes Association criteria in the diagnosis of glucose intolerance among high-risk Omani subjects.
Type 2 diabetes mellitus is highly prevalent in the rapidly growing Omani population. The American Diabetes Association (ADA) has recommended new criteria for Type 2 diabetes, but the new criteria have been challenged as inadequate. We measured the sensitivityand specificity of theADA criteria compared with World Health Organization (WHO) criteria for the diagnosis of abnormal glucose intolerance in Omani subjects. Subjects not known to have diabetes were recruited from the Lipid and Endocrine Clinics at Sultan Qaboos University Hospital between 1999 and 2001. Fasting and 2-hour post-75g oral glucose tolerance test (OGTT) glucose levels were measured according to WHO criteria. 176 subjects were recruited for the study. WHO and the ADA criteria were in agreement for 104 out of 115 normal glucose tolerance (NGT), 4 out of 38 impaired glucose tolerance (IGT), and 14 out of 23 diabetic tolerance glucose (DGT) corresponding to a sensitivity of 90%, 10%, and 61% for NGT, IGT, and DGT, respectively. Compared with WHO criteria, the ADA criteria had 30% sensitivity and 90% specificity overall. Comparing fasting glucose cutoff values for the diagnosis of IGT, a cut-off of 5.9 mmol/L yielded the best diagnostic sensitivity and specificity compared to the 6.1 mmol/L recommended by the ADA criteria as determined by the receiver-operating characteristics (ROC), with an area under the curve of 0.677 vs. 0.387, respectively. The ADA criteria had poor sensitivity in the detection of impaired glucose tolerance in high-risk Omani subjects compared with WHO criteria.


Detectivity enhancement in THz electrooptical sampling.
We demonstrate and discuss a simple scheme that significantly enhances the detectivity of THz electro-optical sampling by introducing a sequence of Brewster windows that increases the ellipticity of the probe beam. By varying the window material or the number of Brewster windows, the enhancement factor can be adjusted; we demonstrate an enhancement factor of ≈20 with four ZnSe Brewster windows. The scheme is particularly useful when very small THz fields are to be measured in connection with low-repetition rate amplified Ti:S laser systems.


Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial.
Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed. To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer. This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017. Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients. The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population. Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment. Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial. ClinicalTrials.gov identifier: NCT02392637.


Physician respect for patients with obesity.
Obesity stigma is common in our society, and a general stigma towards obesity has also been documented in physicians. We hypothesized that physician respect for patients would be lower in patients with higher body mass index (BMI). We analyzed data from the baseline visit of 40 physicians and 238 patients enrolled in a randomized controlled trial of patient-physician communication. The independent variable was BMI, and the outcome was physician respect for the patient. We performed Poisson regression analyses with robust variance estimates, accounting for clustering of patients within physicians, to examine the association between BMI and physician ratings of respect for particular patients. The mean (SD) BMI of the patients was 32.9(8.1) kg/m(2). Physicians had low respect for 39% of the participants. Higher BMI was significantly and negatively associated with respect [prevalence ratio (PrR) 0.83, 95% CI: 0.73-0.95; p = 0.006; per 10 kg/m(2) increase in BMI]. BMI remained significantly associated with respect after adjustment for patient age and gender (PrR 0.86, 95%CI: 0.74-1.00; p = 0.049). We found that higher patient BMI was associated with lower physician respect. Further research is needed to understand if lower physician respect for patients with higher BMI adversely affects the quality of care.


Beyond Membrane Protein Structure: Drug Discovery, Dynamics and Difficulties.
Most of the previous content of this book has focused on obtaining the structures of membrane proteins. In this chapter we explore how those structures can be further used in two key ways. The first is their use in structure based drug design (SBDD) and the second is how they can be used to extend our understanding of their functional activity via the use of molecular dynamics. Both aspects now heavily rely on computations. This area is vast, and alas, too large to consider in depth in a single book chapter. Thus where appropriate we have referred the reader to recent reviews for deeper assessment of the field. We discuss progress via the use of examples from two main drug target areas; G-protein coupled receptors (GPCRs) and ion channels. We end with a discussion of some of the main challenges in the area.